The global emergence of highly drug resistant tuberculosis (MDR and XDR TB) poses a serious and growing threat to world health. New classes of TB drugs are urgently needed to combat these infections, but new regimens comprised of 2 or more members of such new classes of TB drugs are thought to have the greatest chances of long-term success. The current paradigm is to study new drugs individually, but this does not inform the development of new regimens. Moreover, the perceived lack of a viable market has deterred many companies from developing new drugs for TB. This project is a unique partnership between big pharma, biotech and academia that will examine a novel 3-drug combination of new agents in which 2 drugs attack different components of the bacterial cell wall and the third blocks bacterial protein synthesis. Two of the drugs are currently in separate clinical development programs for a TB indication. The third is in clinical development for indications other than TB and would not likely be developed for TB without independent support. This proposed drug combination will be studied intensively to with regard its ability to rapidly kill TB bacteria and prevent emergence of resistance. These characteristics as well as the optimal combinations and dosing regimens will be determined using innovative liquid culture and cell culture systems and a well established mouse model in an effort integrated with sophisticated mathematical modeling techniques. Additional new agents in clinical development may be incorporated as the project evolves. The goal is to identify potent drug combinations that are likely to be safe and effective and that could be subsequently tested in human clinical trials. New drug regimens comprised of 2 or more new drug classes are urgently needed to combat the serious and growing global health emergency posed by highly drug resistant tuberculosis (MDR and XDR TB). This project proposes a unique partnership between a major pharmaceutical company, a small biotech company and 2 academic institutions to examine a novel combination of 3 new agents expected to have a synergistic killing effect against TB bacteria. The goal is to identify potent drug combinations that are likely to be safe and effective and that could be subsequently tested in human clinical trials.